Alkyl phenols have a broad range of medicinal properties ranging from central nervous system (CNS) effects to antioxidant activities. The effects of alkyl phenols on the CNS are generally sedative in nature. For example, the dialkylphenol, propofol (2,6-diisopropylphenol is used as anesthetic agent in both humans and animals. This compound also serves as a muscle relaxant, anti-epileptic, anti-emetic, anti-spasmotic and as a bronchodilator. Importantly, recent studies demonstrate that administration of propofol to subjects leads to cessation of migraines (Kruse et al., 2000, Headache 40: 224-230).
Diisopropylphenol also has uses in the treatment of pathologies relating to the presence of free oxygen radicals (see, see, e.g., U.S. Pat. No. 5,308,874; U.S. Pat. No. 5,461,080; and Aarts et al., 1995, FEBS Let. 357(1): 83-5). For example, propofol has been used to inhibit inflammatory responses of the upper respiratory tract due to oxidative stress (see, e.g., Zaloga et al., The Internet Journal of Emergency and Intensive Care Medicine™ ISSN 1092-4051; Borgeat et al., 1992, American J. of Gastroent. 87(5): 672-674). Propofol also has been shown to repair neural damage caused by free oxygen radicals in vitro (Sagara et al., 1999, J Neurochem. 73(6): 2524-30; Jevtovic-Todorovic et al., 2001, Brain Res. 913(2): 185-9) and has been used in vivo to treat head injury (see, e.g., Kelly et al., Journal of Neurosurgery 90: 1042-1052, 1999).
The only recognized method for delivery of alkylphenols is by intravenous (iv) injection in a lipid-based emulsion. After iv administration, propofol is rapidly distributed from the blood into highly perfused areas such as heart, lung, and liver. Propofol also is rapidly distributed to tissues because of its high solubility in lipids. This high solubility enables propofol to cross the blood-brain barrier easily. However, the oil emulsion forms of propofol contain a high concentration of lipids that potentiate hyperlipidemia, and frequently cause pain upon injection (see, e.g., Lowrey et al., 1996, Nutr Clin Pract. 11: 147-149; Kress et al., Am. J. Respir. Crit. Care Med. 153: 1012-1018; Cerra et al., 1997, Chest. 111: 769-777).
An inhalant form of an alkylphenol is desirable as a pre-anesthetic or anesthetic agent because no iv injection is required. In addition, an inhalable form of an alkyl phenol is desirable for treatment of respiratory disorders and migraines, where rapid action is desired. However, delivery of alkylphenols by inhalation has been problematic because alkyl phenols generally are not sufficiently volatile at low temperature. Therefore, inhalable forms of propofol must be heated or delivered in formulations in which they are soluble and can be aerosolized. For example, aerosols comprising lipid-based microdroplets of propofol have been reported (see, e.g., U.S. Patent Application No. 20010004644) as well as formulations comprising propofol dissolved in tetrafluoroethane (see, e.g., U.S. Pat. No. 5,496,537). However, formulations that contain emulsifiers or solubilizers cause problems such as allergic complications (see, e.g., Briggs et al., Anesthesis 37: 1099) and contamination (McHugh et al., 1995, Can J. Anaesth. 42(9): 801-804). Water soluble pro-drug forms of propofol esters have been described (see, e.g., U.S. Pat. No. 6,254,853); however, these compounds generally are administered as aerosols in the presence of both a surfactant and a propellant and must be metabolized first in the body to a bioactive form. Further, it would be unlikely that propofol pro-drugs would provide sufficient propofol blood concentrations to induce general anesthesia in surgical patients.